Hepatic encephalopathy (HE) is a condition that can affect the brain in people who have chronic liver disease. It happens when a damaged liver cannot effectively filter ammonia and other toxins out of the blood. These toxins can build up in the bloodstream and travel to the brain, where they may cause changes in thinking, behavior, mood, and personality.
Confusion and other symptoms can range from barely noticeable (covert) to more obvious changes that other people may notice. When symptoms are more noticeable, it’s called overt hepatic encephalopathy (OHE). If an overt episode happens, you may need to stay in the hospital to treat it.
Lactulose is commonly used to help stop sudden episodes of OHE. It helps lower ammonia levels. Once your symptoms begin to improve, your health care provider may also prescribe a tablet called Xifaxan.
Xifaxan (rifaximin) is a medicine that can help reduce the risk of having more overt episodes. It is FDA-approved to reduce the risk of OHE coming back.
This article explores how Xifaxan works, what studies show about how well it works for OHE, and tips for managing side effects.
How Does Xifaxan Work for Hepatic Encephalopathy?
Xifaxan contains rifaximin, an antibiotic that works mainly in the gut and may help regulate gut bacteria. However, the exact way it helps reduce symptoms of HE is not fully understood.
Your intestines contain bacteria that your body needs for digestion, gut health, and other purposes. But these bacteria release waste products that can be toxic if they are not properly filtered out of your body by the liver. If the liver is not working as well as it should, toxins can build up in the blood and reach the brain, leading to symptoms of HE such as confusion and mood changes.
Xifaxan is thought to work for HE by slowing the growth of certain gut bacteria that make waste products. It does this by blocking a step in the process bacteria use to make proteins. Without these proteins, the bacteria cannot grow or survive, so the amount of waste released into the gut is reduced. This may help lower the amount of toxins that enter the blood.
Only a small amount of Xifaxan is absorbed into the bloodstream. Most of it stays in the gut, which helps limit its effects on the rest of the body.
How Do I Take Xifaxan for Hepatic Encephalopathy?
Xifaxan comes as a tablet that you swallow. You can take it with or without food.
For adults with HE, the recommended dosage of Xifaxan is 550 mg two times a day. Always be sure to follow your health care provider’s instructions, as some specialists may prescribe a different dosage.
How Was Xifaxan Studied for Hepatic Encephalopathy?
Xifaxan was studied in adults with chronic liver disease who had a history of HE. Two six-month clinical studies evaluated how Xifaxan worked to help reduce the risk of OHE coming back.
Study 1. In the first study, people with chronic liver disease could join the study if they had at least two episodes of HE within the previous six months.
The study included 299 adults from the United States, Canada, and Russia. Of the 299 participants:
- The average age was 56 years, with a range of21- 82 years
- 61% were men, and the rest were women.
- Most (86%) were White, 4% were Asian, 4% were Black/African American, 3% were American Indian/Alaskan Native, 1% were Native Hawaiian/Pacific Islander, and 2% identified as other races.
At the start of the study (baseline), all participants were in remission. This means they had no symptoms or only mild symptoms of OHE. Also at baseline:
- 67% of participants had a Conn score of 0, indicating no obvious signs of HE.
- 68% had an asterixis grade of 0, indicating no flapping tremor.
- Based on Model for End-Stage Liver Disease (MELD) scores at baseline, 27% of participants had scores of 10 or lower, and 64% had scores between 11 and 18. No participants had MELD scores greater than 25. Higher MELD scores mean more severe liver disease.
- Some (9%) of participants had severe liver disease (classified as Child-Pugh Class C).
The participants were randomly assigned to take either Xifaxan or a placebo (a tablet with no active medicine in it). No one knew which one they were taking. Most participants in both the Xifaxan and placebo groups also took lactulose.
The main goal of the study was to measure how long it took before a person had their first breakthrough episode of HE. A breakthrough episode was defined as a clear worsening of brain function and an increase in Conn score. Another important goal was to measure how long it took before a person was hospitalized because of HE.
In other words, the researchers wanted to see how long it took until people had a sudden worsening of HE symptoms, such as confusion, obvious personality changes, or strange behavior.
Study 2. This was an open-label study, meaning the participants and researchers knew which treatment was being used. The study included 222 adults who had experienced at least one episode of OHE, defined as a Conn score of 2 or higher, within the previous six months. The participant groups in study 2 had similar age, sex, and racial backgrounds to those in study 1.
People were randomly assigned to take either Xifaxan only or a combination of Xifaxan plus lactulose. As in the first study, the main goal of this study was to measure the time until the first breakthrough episode of OHE.
What Are the Benefits of Xifaxan Based on Studies?
The clinical study results showed that Xifaxan is an effective treatment for lowering the risk of OHE episodes coming back in adults with chronic liver disease.
Study 1. The first study found that fewer people taking Xifaxan had a new episode of OHE compared with those taking a placebo. After six months, 22% of the participants in the Xifaxan group had a breakthrough episode of OHE. In comparison, 46% of those in the placebo group had a breakthrough episode during the same time period. This is a risk difference of 24%, which means that out of every 100 people treated, 24 fewer people had a breakthrough episode on Xifaxan.
Overall, Xifaxan reduced the risk of OHE coming back by 58% during the six-month treatment period.
The study also tracked hospitalizations related to HE. In the Xifaxan group, 14% had a hospitalization related to HE. In the placebo group, 23% had an HE- related hospitalization. This is a risk difference of 9%, meaning about 9 fewer people out of 100 were hospitalized for HE.
Overall, Xifaxan reduced the risk of HE-related hospitalizations by 50% over six months.
Study 2. During the six-month study, fewer people had a breakthrough episode when Xifaxan was taken along with lactulose. In the group taking both Xifaxan and lactulose, 14% had a breakthrough episode, compared with 25% of people taking Xifaxan alone.
Your results may differ from what was seen in studies.
How Strong Is the Evidence for Xifaxan? What Is Its Place in Therapy?
According to experts from the American Association for the Study of Liver Diseases, lactulose is the first-choice treatment for episodes of OHE. These experts recommend Xifaxan as an add-on treatment to help prevent symptoms from coming back. Your health care provider can let you know if Xifaxan may be right for you.
Like other medicines, Xifaxan can cause side effects. Not everyone will have the same side effects, and many are manageable. A health care provider can help monitor side effects and suggest next steps if needed.
What Can I Do to Prevent or Manage Side Effects of Xifaxan?
The most common side effects reported in adults with HE include swelling in the arms or legs, nausea, constipation, dizziness, fatigue, urinary tract infection, trouble sleeping, anemia, itching, and fluid buildup in the belly. Let a health care provider know if side effects are bothersome or do not improve.
Swelling. Swelling and fluid retention were among the most common side effects reported with Xifaxan. Limiting salty foods may help reduce fluid retention. Elevating the legs when sitting and wearing compression socks, if recommended by a health care provider, may also help. Watch for changes in weight and report new or worsening symptoms to your health care team.
Digestive symptoms. Nausea and constipation were among the most common side effects seen in studies of Xifaxan. If you also take lactulose, your health care provider may help you adjust the lactulose dose until your stool is soft, which may make it easier to pass. Eating bland foods and smaller meals may help minimize nausea. Tell a health care provider if your symptoms interfere with eating, comfort, or daily activities.
Dizziness and fatigue.Dizziness and tiredness were also common side effects. If you feel dizzy, sit or lie down right away. Standing up slowly and getting enough rest can help. Use caution with activities that require alertness and inform a health care provider if symptoms continue.
Trouble sleeping and itching. Trouble sleeping and itchiness were commonly reported side effects. Itchy skin is also a common symptom of liver problems. Try using moisturizers to prevent dry skin, wearing loose clothing, and bathing in warm rather than hot water. It’s also a good idea to keep your fingernails short to help lessen skin damage from scratching. For insomnia, making adjustments to your bedtime routine can help you sleep better. Let a health care provider know if these symptoms affect sleep or quality of life.
Antibiotic-related diarrhea. While rare, severe diarrhea caused by a bacteria known as C. diff has been reported with many antibiotics, including Xifaxan. This type of diarrhea can be serious. Symptoms may include watery or bloody stools, with or without stomach cramps or fever. Diarrhea can happen during treatment or weeks to months after stopping Xifaxan. If diarrhea starts, does not improve, or gets worse, contact a health care provider as soon as possible.
This is not a complete list of possible Xifaxan side effects. Contact your health care provider if you have symptoms that concern you while taking Xifaxan.
What Do We Know About the Long-Term Safety of Xifaxan?
Long-term safety of Xifaxan was studied in adults with HE who took the medicine for up to two years (24 months). The study included 392 people; some had taken part in an earlier six-month study. In this study, some people took rifaximin for only a few days, while others took it for up to about four years. The middle value for how long people took the medicine was around 14 months.
Overall, the types and rates of side effects seen with long-term Xifaxan use were similar to those reported in the earlier six-month study. There was no increase in infections, including C. diff, and no increase in bacterial resistance. Rates of hospitalizations related to HE stayed low during long-term treatment and were lower than in people who had taken a placebo in the earlier study. These results suggest that long-term use of Xifaxan may help reduce hospitalizations without adding new safety concerns.
Is There Any Cost Assistance Available?
A copay savings program is available from Salix Pharmaceuticals, the maker of Xifaxan. It may reduce the amount you pay. Whether you qualify to enroll may depend on if you have insurance and what type of insurance you have. Visit this website to see if you are eligible for copay savings. You can also call 866-943-2926 to speak with someone about financial support options.
